1 Abstract. 2 In this competing revision we propose to expand the scope of the currently funded multi-site 3 Phase III clinical trial, IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of 4 Exercise) to include measurement of A? following a 12-month physical activity (PA) intervention. 5 Despite an appreciation for the importance of A? accumulation in AD, there are currently no 6 effective treatments to slow or reverse deposition. Moderate intensity PA is one of the most 7 promising non-pharmaceutical approaches for mitigating age-related cognitive decline and 8 reducing risk for neurodegenerative conditions like AD. Unfortunately, the effectiveness of PA 9 remains a matter of continued skepticism because of the lack of a well-controlled Phase III 10 clinical trial. To address this continued skepticism, our team developed a Phase III clinical trial 11 called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise). This 12 study, funded in 2016, was designed to definitively address whether PA improves cognitive and 13 brain health. The IGNITE study was designed to address several major questions including 14 whether the presence of A? moderates the impact of the exercise intervention on cognitive or 15 other brain outcomes (e.g., hippocampal volume). The IGNITE study was also designed to 16 examine potential mechanisms of exercise on the brain. We have a unique opportunity to add 17 PET A? at follow-up to the ongoing IGNITE study which will allow us to test a number of critical 18 aims. Thus, this competing revision will leverage the size and rigor of the IGNITE trial (N = 639) 19 to examine whether 12 months of moderate intensity PA modifies A? pathology among 20 cognitively healthy older adults. Specifically, we will test: (a) whether a 12-month PA 21 intervention attenuates A? levels compared to a non-aerobic control group and (b) whether 22 changes occur in a dose-dependent manner. We will also test whether changes in A? mediate 23 exercise-induced changes in cognition and will test whether exercise-induced changes in 24 cardiometabolic, inflammatory, and neurotrophic factors statistically mediate changes in A? 25 burden. This proposal represents a unique opportunity to resolve whether PA could be applied 26 as a low cost, easily disseminated approach to mitigate A? accumulation. The outcomes of 27 IGNITE will have enormous implications for the way we approach treatment and prevention of 28 AD, and has the potential to advance the fields of gerontology, neuroscience, and public health. 29 30 31 32